14‐3‐3σ/Stratifin and p21 limit AKT‐related malignant progression in skin carcinogenesis following MDM2‐associated p53 loss
To study mechanisms driving/inhibiting skin carcinogenesis, stage‐specific expression of 14‐3‐3σ (Stratifin) was analyzed in skin carcinogenesis driven by activated rasHa/fos expression (HK1.ras/fos) and ablation of PTEN‐mediated AKT regulation (K14.creP/Δ5PTENflx/flx). Consistent with 14‐3‐3σ roles...
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| Veröffentlicht in: | Molecular carcinogenesis 2024-09, Vol.63 (9), p.1768-1782 |
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| creator | McMenemy, Carol M. Guo, Dajiang Quinn, Jean A. Greenhalgh, David A. |
| description | To study mechanisms driving/inhibiting skin carcinogenesis, stage‐specific expression of 14‐3‐3σ (Stratifin) was analyzed in skin carcinogenesis driven by activated rasHa/fos expression (HK1.ras/fos) and ablation of PTEN‐mediated AKT regulation (K14.creP/Δ5PTENflx/flx). Consistent with 14‐3‐3σ roles in epidermal differentiation, HK1.ras hyperplasia and papillomas displayed elevated 14‐3‐3σ expression in supra‐basal keratinocytes, paralleled by supra‐basal p‐MDM2166 activation and sporadic p‐AKT473 expression. In bi‐genic HK1.fos/Δ5PTENflx/flx hyperplasia, basal‐layer 14‐3‐3σ expression appeared, and alongside p53/p21, was associated with keratinocyte differentiation and keratoacanthoma etiology. Tri‐genic HK1.ras/fos‐Δ5PTENflx/flx hyperplasia/papillomas initially displayed increased basal‐layer 14‐3‐3σ, suggesting attempts to maintain supra‐basal p‐MDM2166 and protect basal‐layer p53. However, HK1.ras/fos‐Δ5PTENflx/flx papillomas exhibited increasing basal‐layer p‐MDM2166 activation that reduced p53, which coincided with malignant conversion. Despite p53 loss, 14‐3‐3σ expression persisted in well‐differentiated squamous cell carcinomas (wdSCCs) and alongside elevated p21, limited malignant progression via inhibiting p‐AKT1473 expression; until 14‐3‐3σ/p21 loss facilitated progression to aggressive SCC exhibiting uniform p‐AKT1473. Analysis of TPA‐promoted HK1.ras‐Δ5PTENflx/flx mouse skin, demonstrated early loss of 14‐3‐3σ/p53/p21 in hyperplasia and papillomas, with increased p‐MDM2166/p‐AKT1473 that resulted in rapid malignant conversion and progression to poorly differentiated SCC. In 2D/3D cultures, membranous 14‐3‐3σ expression observed in normal HaCaT and SP1ras61 papilloma keratinocytes was unexpectedly detected in malignant T52ras61/v‐fos SCC cells cultured in monolayers, but not invasive 3D‐cells. Collectively, these data suggest 14‐3‐3σ/Stratifin exerts suppressive roles in papillomatogenesis via MDM2/p53‐dependent mechanisms; while persistent p53‐independent expression in early wdSCC may involve p21‐mediated AKT1 inhibition to limit malignant progression. |
| doi_str_mv | 10.1002/mc.23771 |
| format | Article |
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Consistent with 14‐3‐3σ roles in epidermal differentiation, HK1.ras hyperplasia and papillomas displayed elevated 14‐3‐3σ expression in supra‐basal keratinocytes, paralleled by supra‐basal p‐MDM2166 activation and sporadic p‐AKT473 expression. In bi‐genic HK1.fos/Δ5PTENflx/flx hyperplasia, basal‐layer 14‐3‐3σ expression appeared, and alongside p53/p21, was associated with keratinocyte differentiation and keratoacanthoma etiology. Tri‐genic HK1.ras/fos‐Δ5PTENflx/flx hyperplasia/papillomas initially displayed increased basal‐layer 14‐3‐3σ, suggesting attempts to maintain supra‐basal p‐MDM2166 and protect basal‐layer p53. However, HK1.ras/fos‐Δ5PTENflx/flx papillomas exhibited increasing basal‐layer p‐MDM2166 activation that reduced p53, which coincided with malignant conversion. Despite p53 loss, 14‐3‐3σ expression persisted in well‐differentiated squamous cell carcinomas (wdSCCs) and alongside elevated p21, limited malignant progression via inhibiting p‐AKT1473 expression; until 14‐3‐3σ/p21 loss facilitated progression to aggressive SCC exhibiting uniform p‐AKT1473. Analysis of TPA‐promoted HK1.ras‐Δ5PTENflx/flx mouse skin, demonstrated early loss of 14‐3‐3σ/p53/p21 in hyperplasia and papillomas, with increased p‐MDM2166/p‐AKT1473 that resulted in rapid malignant conversion and progression to poorly differentiated SCC. In 2D/3D cultures, membranous 14‐3‐3σ expression observed in normal HaCaT and SP1ras61 papilloma keratinocytes was unexpectedly detected in malignant T52ras61/v‐fos SCC cells cultured in monolayers, but not invasive 3D‐cells. Collectively, these data suggest 14‐3‐3σ/Stratifin exerts suppressive roles in papillomatogenesis via MDM2/p53‐dependent mechanisms; while persistent p53‐independent expression in early wdSCC may involve p21‐mediated AKT1 inhibition to limit malignant progression.</description><identifier>ISSN: 0899-1987</identifier><identifier>ISSN: 1098-2744</identifier><identifier>EISSN: 1098-2744</identifier><identifier>DOI: 10.1002/mc.23771</identifier><identifier>PMID: 38869281</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>14-3-3 Proteins - genetics ; 14-3-3 Proteins - metabolism ; AKT protein ; AKT1 protein ; Animals ; Carcinogenesis ; Carcinogenesis - genetics ; Carcinogenesis - metabolism ; Carcinogenesis - pathology ; Cell differentiation ; Cyclin-dependent kinase inhibitor p21 ; Cyclin-Dependent Kinase Inhibitor p21 - genetics ; Cyclin-Dependent Kinase Inhibitor p21 - metabolism ; Disease Progression ; Exoribonucleases - genetics ; Exoribonucleases - metabolism ; fos ; Gene expression ; Gene Expression Regulation, Neoplastic ; Humans ; Hyperplasia ; Keratinocytes ; Keratinocytes - metabolism ; Keratinocytes - pathology ; keratoacanthoma ; MDM2 protein ; Mice ; organotypic culture ; Papilloma ; Proto-Oncogene Proteins c-akt - metabolism ; Proto-Oncogene Proteins c-mdm2 - genetics ; Proto-Oncogene Proteins c-mdm2 - metabolism ; PTEN ; PTEN protein ; ras ; Skin ; Skin cancer ; skin carcinogenesis ; Skin Neoplasms - genetics ; Skin Neoplasms - metabolism ; Skin Neoplasms - pathology ; Squamous cell carcinoma ; Stratifin ; TPA promotion ; transgenic mouse ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism</subject><ispartof>Molecular carcinogenesis, 2024-09, Vol.63 (9), p.1768-1782</ispartof><rights>2024 The Author(s). published by Wiley Periodicals LLC.</rights><rights>2024 The Author(s). Molecular Carcinogenesis published by Wiley Periodicals LLC.</rights><rights>2024. This article is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c2741-1a6c03a035055be9e9a1abfa5e3f65491819d21f11207ca9f46ad2907bcd8ddc3</cites><orcidid>0000-0002-6737-2744</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fmc.23771$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fmc.23771$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38869281$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>McMenemy, Carol M.</creatorcontrib><creatorcontrib>Guo, Dajiang</creatorcontrib><creatorcontrib>Quinn, Jean A.</creatorcontrib><creatorcontrib>Greenhalgh, David A.</creatorcontrib><title>14‐3‐3σ/Stratifin and p21 limit AKT‐related malignant progression in skin carcinogenesis following MDM2‐associated p53 loss</title><title>Molecular carcinogenesis</title><addtitle>Mol Carcinog</addtitle><description>To study mechanisms driving/inhibiting skin carcinogenesis, stage‐specific expression of 14‐3‐3σ (Stratifin) was analyzed in skin carcinogenesis driven by activated rasHa/fos expression (HK1.ras/fos) and ablation of PTEN‐mediated AKT regulation (K14.creP/Δ5PTENflx/flx). Consistent with 14‐3‐3σ roles in epidermal differentiation, HK1.ras hyperplasia and papillomas displayed elevated 14‐3‐3σ expression in supra‐basal keratinocytes, paralleled by supra‐basal p‐MDM2166 activation and sporadic p‐AKT473 expression. In bi‐genic HK1.fos/Δ5PTENflx/flx hyperplasia, basal‐layer 14‐3‐3σ expression appeared, and alongside p53/p21, was associated with keratinocyte differentiation and keratoacanthoma etiology. Tri‐genic HK1.ras/fos‐Δ5PTENflx/flx hyperplasia/papillomas initially displayed increased basal‐layer 14‐3‐3σ, suggesting attempts to maintain supra‐basal p‐MDM2166 and protect basal‐layer p53. However, HK1.ras/fos‐Δ5PTENflx/flx papillomas exhibited increasing basal‐layer p‐MDM2166 activation that reduced p53, which coincided with malignant conversion. Despite p53 loss, 14‐3‐3σ expression persisted in well‐differentiated squamous cell carcinomas (wdSCCs) and alongside elevated p21, limited malignant progression via inhibiting p‐AKT1473 expression; until 14‐3‐3σ/p21 loss facilitated progression to aggressive SCC exhibiting uniform p‐AKT1473. Analysis of TPA‐promoted HK1.ras‐Δ5PTENflx/flx mouse skin, demonstrated early loss of 14‐3‐3σ/p53/p21 in hyperplasia and papillomas, with increased p‐MDM2166/p‐AKT1473 that resulted in rapid malignant conversion and progression to poorly differentiated SCC. In 2D/3D cultures, membranous 14‐3‐3σ expression observed in normal HaCaT and SP1ras61 papilloma keratinocytes was unexpectedly detected in malignant T52ras61/v‐fos SCC cells cultured in monolayers, but not invasive 3D‐cells. Collectively, these data suggest 14‐3‐3σ/Stratifin exerts suppressive roles in papillomatogenesis via MDM2/p53‐dependent mechanisms; while persistent p53‐independent expression in early wdSCC may involve p21‐mediated AKT1 inhibition to limit malignant progression.</description><subject>14-3-3 Proteins - genetics</subject><subject>14-3-3 Proteins - metabolism</subject><subject>AKT protein</subject><subject>AKT1 protein</subject><subject>Animals</subject><subject>Carcinogenesis</subject><subject>Carcinogenesis - genetics</subject><subject>Carcinogenesis - metabolism</subject><subject>Carcinogenesis - pathology</subject><subject>Cell differentiation</subject><subject>Cyclin-dependent kinase inhibitor p21</subject><subject>Cyclin-Dependent Kinase Inhibitor p21 - genetics</subject><subject>Cyclin-Dependent Kinase Inhibitor p21 - metabolism</subject><subject>Disease Progression</subject><subject>Exoribonucleases - genetics</subject><subject>Exoribonucleases - metabolism</subject><subject>fos</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Humans</subject><subject>Hyperplasia</subject><subject>Keratinocytes</subject><subject>Keratinocytes - metabolism</subject><subject>Keratinocytes - pathology</subject><subject>keratoacanthoma</subject><subject>MDM2 protein</subject><subject>Mice</subject><subject>organotypic culture</subject><subject>Papilloma</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Proto-Oncogene Proteins c-mdm2 - genetics</subject><subject>Proto-Oncogene Proteins c-mdm2 - metabolism</subject><subject>PTEN</subject><subject>PTEN protein</subject><subject>ras</subject><subject>Skin</subject><subject>Skin cancer</subject><subject>skin carcinogenesis</subject><subject>Skin Neoplasms - genetics</subject><subject>Skin Neoplasms - metabolism</subject><subject>Skin Neoplasms - pathology</subject><subject>Squamous cell carcinoma</subject><subject>Stratifin</subject><subject>TPA promotion</subject><subject>transgenic mouse</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><issn>0899-1987</issn><issn>1098-2744</issn><issn>1098-2744</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNp1kUFuFDEQRS0EIkNA4gTIEhs2nbjsdtteRhMCiIxYENatGrd75OC2B7tHUXZI5ADcjDtwEpxMAAmJRVVtXj1V6RPyHNgRMMaPJ3vEhVLwgCyAGd1w1bYPyYJpYxowWh2QJ6VcMgagJHtMDoTWneEaFuQG2p9fv4vb-vHt-OOccfajjxTjQLccaPCTn-nJ-4tKZBdwdgOdMPhNxDjTbU6b7ErxKdK6VD7XZjFbH9PGRVd8oWMKIV35uKGr0xWvFiwlWX8n2kpBQyrlKXk0Yiju2f08JJ_OXl8s3zbnH968W56cN7Y-BA1gZ5lAJiSTcu2MMwi4HlE6MXayNaDBDBxGAM6URTO2HQ7cMLW2gx4GKw7Jq7233v1l58rcT75YFwJGl3alF6xTBtpW64q-_Ae9TLsc63WVMkIqw5X8K7S5vpHd2G-znzBf98D622T6yfZ3yVT0xb1wt57c8Af8HUUFmj1w5YO7_q-oXy33wl-G2Jpj</recordid><startdate>202409</startdate><enddate>202409</enddate><creator>McMenemy, Carol M.</creator><creator>Guo, Dajiang</creator><creator>Quinn, Jean A.</creator><creator>Greenhalgh, David A.</creator><general>Wiley Subscription Services, Inc</general><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TM</scope><scope>7TO</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-6737-2744</orcidid></search><sort><creationdate>202409</creationdate><title>14‐3‐3σ/Stratifin and p21 limit AKT‐related malignant progression in skin carcinogenesis following MDM2‐associated p53 loss</title><author>McMenemy, Carol M. ; Guo, Dajiang ; Quinn, Jean A. ; Greenhalgh, David A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c2741-1a6c03a035055be9e9a1abfa5e3f65491819d21f11207ca9f46ad2907bcd8ddc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>14-3-3 Proteins - genetics</topic><topic>14-3-3 Proteins - metabolism</topic><topic>AKT protein</topic><topic>AKT1 protein</topic><topic>Animals</topic><topic>Carcinogenesis</topic><topic>Carcinogenesis - genetics</topic><topic>Carcinogenesis - metabolism</topic><topic>Carcinogenesis - pathology</topic><topic>Cell differentiation</topic><topic>Cyclin-dependent kinase inhibitor p21</topic><topic>Cyclin-Dependent Kinase Inhibitor p21 - genetics</topic><topic>Cyclin-Dependent Kinase Inhibitor p21 - metabolism</topic><topic>Disease Progression</topic><topic>Exoribonucleases - genetics</topic><topic>Exoribonucleases - metabolism</topic><topic>fos</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Humans</topic><topic>Hyperplasia</topic><topic>Keratinocytes</topic><topic>Keratinocytes - metabolism</topic><topic>Keratinocytes - pathology</topic><topic>keratoacanthoma</topic><topic>MDM2 protein</topic><topic>Mice</topic><topic>organotypic culture</topic><topic>Papilloma</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Proto-Oncogene Proteins c-mdm2 - genetics</topic><topic>Proto-Oncogene Proteins c-mdm2 - metabolism</topic><topic>PTEN</topic><topic>PTEN protein</topic><topic>ras</topic><topic>Skin</topic><topic>Skin cancer</topic><topic>skin carcinogenesis</topic><topic>Skin Neoplasms - genetics</topic><topic>Skin Neoplasms - metabolism</topic><topic>Skin Neoplasms - pathology</topic><topic>Squamous cell carcinoma</topic><topic>Stratifin</topic><topic>TPA promotion</topic><topic>transgenic mouse</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>McMenemy, Carol M.</creatorcontrib><creatorcontrib>Guo, Dajiang</creatorcontrib><creatorcontrib>Quinn, Jean A.</creatorcontrib><creatorcontrib>Greenhalgh, David A.</creatorcontrib><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Online Library Free Content</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular carcinogenesis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>McMenemy, Carol M.</au><au>Guo, Dajiang</au><au>Quinn, Jean A.</au><au>Greenhalgh, David A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>14‐3‐3σ/Stratifin and p21 limit AKT‐related malignant progression in skin carcinogenesis following MDM2‐associated p53 loss</atitle><jtitle>Molecular carcinogenesis</jtitle><addtitle>Mol Carcinog</addtitle><date>2024-09</date><risdate>2024</risdate><volume>63</volume><issue>9</issue><spage>1768</spage><epage>1782</epage><pages>1768-1782</pages><issn>0899-1987</issn><issn>1098-2744</issn><eissn>1098-2744</eissn><abstract>To study mechanisms driving/inhibiting skin carcinogenesis, stage‐specific expression of 14‐3‐3σ (Stratifin) was analyzed in skin carcinogenesis driven by activated rasHa/fos expression (HK1.ras/fos) and ablation of PTEN‐mediated AKT regulation (K14.creP/Δ5PTENflx/flx). Consistent with 14‐3‐3σ roles in epidermal differentiation, HK1.ras hyperplasia and papillomas displayed elevated 14‐3‐3σ expression in supra‐basal keratinocytes, paralleled by supra‐basal p‐MDM2166 activation and sporadic p‐AKT473 expression. In bi‐genic HK1.fos/Δ5PTENflx/flx hyperplasia, basal‐layer 14‐3‐3σ expression appeared, and alongside p53/p21, was associated with keratinocyte differentiation and keratoacanthoma etiology. Tri‐genic HK1.ras/fos‐Δ5PTENflx/flx hyperplasia/papillomas initially displayed increased basal‐layer 14‐3‐3σ, suggesting attempts to maintain supra‐basal p‐MDM2166 and protect basal‐layer p53. However, HK1.ras/fos‐Δ5PTENflx/flx papillomas exhibited increasing basal‐layer p‐MDM2166 activation that reduced p53, which coincided with malignant conversion. Despite p53 loss, 14‐3‐3σ expression persisted in well‐differentiated squamous cell carcinomas (wdSCCs) and alongside elevated p21, limited malignant progression via inhibiting p‐AKT1473 expression; until 14‐3‐3σ/p21 loss facilitated progression to aggressive SCC exhibiting uniform p‐AKT1473. Analysis of TPA‐promoted HK1.ras‐Δ5PTENflx/flx mouse skin, demonstrated early loss of 14‐3‐3σ/p53/p21 in hyperplasia and papillomas, with increased p‐MDM2166/p‐AKT1473 that resulted in rapid malignant conversion and progression to poorly differentiated SCC. In 2D/3D cultures, membranous 14‐3‐3σ expression observed in normal HaCaT and SP1ras61 papilloma keratinocytes was unexpectedly detected in malignant T52ras61/v‐fos SCC cells cultured in monolayers, but not invasive 3D‐cells. Collectively, these data suggest 14‐3‐3σ/Stratifin exerts suppressive roles in papillomatogenesis via MDM2/p53‐dependent mechanisms; while persistent p53‐independent expression in early wdSCC may involve p21‐mediated AKT1 inhibition to limit malignant progression.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>38869281</pmid><doi>10.1002/mc.23771</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-6737-2744</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Molecular carcinogenesis, 2024-09, Vol.63 (9), p.1768-1782 |
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| subjects | 14-3-3 Proteins - genetics 14-3-3 Proteins - metabolism AKT protein AKT1 protein Animals Carcinogenesis Carcinogenesis - genetics Carcinogenesis - metabolism Carcinogenesis - pathology Cell differentiation Cyclin-dependent kinase inhibitor p21 Cyclin-Dependent Kinase Inhibitor p21 - genetics Cyclin-Dependent Kinase Inhibitor p21 - metabolism Disease Progression Exoribonucleases - genetics Exoribonucleases - metabolism fos Gene expression Gene Expression Regulation, Neoplastic Humans Hyperplasia Keratinocytes Keratinocytes - metabolism Keratinocytes - pathology keratoacanthoma MDM2 protein Mice organotypic culture Papilloma Proto-Oncogene Proteins c-akt - metabolism Proto-Oncogene Proteins c-mdm2 - genetics Proto-Oncogene Proteins c-mdm2 - metabolism PTEN PTEN protein ras Skin Skin cancer skin carcinogenesis Skin Neoplasms - genetics Skin Neoplasms - metabolism Skin Neoplasms - pathology Squamous cell carcinoma Stratifin TPA promotion transgenic mouse Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism |
| title | 14‐3‐3σ/Stratifin and p21 limit AKT‐related malignant progression in skin carcinogenesis following MDM2‐associated p53 loss |
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